National Cancer Institute

Fecha de publicación:
Jan 24, 2018

In childhood ependymoma, cancer forms in the tissues of the brain and spinal cord. The cause of ependymoma is unknown. Find out about the molecular and clinical features, diagnosis, prognosis, treatment, and clinical trials for pediatric ependymoma, subependymoma, myxopapillary ependymoma, anaplastic ependymoma, and RELA fusion–positive ependymoma.

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of childhood ependymoma. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.

This summary is reviewed regularly and updated as necessary by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

Childhood Ependymoma Treatment

General Information About Childhood Ependymoma

Primary brain tumors, including ependymomas, are a diverse group of diseases that together constitute the most common solid tumor of childhood. Immunohistochemical analysis, cytogenetic and molecular genetic findings, and measures of mitotic activity are increasingly used in tumor diagnosis and classification. Brain tumors are classified according to histology, but tumor location and extent of spread are important factors that affect treatment and prognosis.

Ependymomas arise from ependymal cells that line the ventricles and passageways in the brain and the center of the spinal cord. Ependymal cells produce cerebrospinal fluid (CSF). These tumors are classified as supratentorial or infratentorial. In children, most ependymomas are infratentorial tumors that arise in or around the fourth ventricle. According to the 2016 revision to the World Health Organization (WHO) classification of tumors of the central nervous system, ependymal tumors are classified into the following five main subtypes:

Subependymoma (WHO Grade I).

Myxopapillary ependymoma (WHO Grade I).

Ependymoma (WHO Grade II).

Ependymoma, fusion–positive (WHO Grade II or Grade III).

Anaplastic ependymoma (WHO Grade III).

The location of the tumor determines the clinical presentation. Treatment begins with surgery. The type of adjuvant therapy given, such as a second surgery, chemotherapy, or radiation therapy, depends on the following:

Subtype of ependymoma.

Whether the tumor was completely removed during the initial surgery.

Whether the tumor has disseminated throughout the central nervous system.

Child's age.

The PDQ childhood brain tumor treatment summaries are organized primarily according to the WHO classification of nervous system tumors. For a full description of the classification of nervous system tumors and a link to the corresponding treatment summary for each type of brain tumor, refer to the PDQ summary on Childhood Brain and Spinal Cord Tumors Treatment Overview.

Incidence

Childhood ependymoma comprises approximately 9% of all childhood brain tumors, representing about 200 cases per year in the United States.

Anatomy

Figure 1. Anatomy of the inside of the brain, showing the pineal and pituitary glands, optic nerve, ventricles (with cerebrospinal fluid shown in blue), and other parts of the brain. The tentorium separates the cerebrum from the cerebellum. The infratentorium (posterior fossa) is the region below the tentorium that contains the brain stem, cerebellum, and fourth ventricle. The supratentorium is the region above the tentorium and denotes the region that contains the cerebrum.

Molecular Features

Molecular characterization studies have identified several biological subtypes of ependymoma based on their distinctive DNA methylation and gene expression profiles and on their distinctive spectrum of genomic alterations (refer to Figure 2).

Approximately two-thirds of childhood ependymomas arise in the posterior fossa, and two major genomically defined subtypes of posterior fossa tumors are recognized. Similarly, most pediatric supratentorial tumors can be categorized into one of two genomic subtypes. These subtypes and their associated clinical characteristics are described below. Among these subtypes, the 2016 World Health Organization (WHO) classification has accepted ependymoma, fusion–positive, as a distinct diagnostic entity.

The most common posterior fossa ependymoma subtype is EPN-PFA and is characterized by the following:

Presentation in young children (median age, 3 years).

Low rates of mutations that affect protein structure (approximately five per genome), with no recurring mutations.

A balanced chromosomal profile (refer to Figure 3) with few chromosomal gains or losses.

Favorable outcome in comparison to EPN-PFA, with 5-year PFS of 73% and overall survival (OS) of 100%.

The largest subset of pediatric supratentorial (ST) ependymomas are characterized by gene fusions involving , a transcriptional factor important in NF-κB pathway activity. This subtype is termed ST-EPN-RELA and is characterized by the following:

Represents approximately 70% of supratentorial ependymomas in children, and presents at a median age of 8 years.

Low rates of mutations that affect protein structure and absence of recurring mutations outside of fusions.

Presence of homozygous deletions of , a known poor prognostic factor for ependymomas, in approximately 15% of cases.

Gain of chromosome 1q, a known poor prognostic factor for ependymomas, in approximately one-quarter of cases.

Unfavorable outcome in comparison to other ependymoma subtypes, with 5-year PFS of 29% and OS of 75%.

Supratentorial clear cell ependymomas with branching capillaries commonly show the fusion, and one series of 20 patients with a median age of 10.4 years showed a relatively favorable prognosis (5-year PFS of 68% and OS of 72%).

A second, less common subset of supratentorial ependymomas, termed ST-EPN-YAP1, has fusions involving and are characterized by the following:

Median age at diagnosis of 1.4 years.

Presence of a gene fusion involving , with being the most common fusion partner.

A relatively stable genome with few chromosomal changes other than the fusion.

Relatively favorable prognosis (although based on small numbers), with a 5-year PFS of 66% and OS of 100%.

Clinical implications of genomic alterations

The absence of recurring mutations in the EPN-PFA and EPN-PFB subtypes at diagnosis precludes using their genomic profiles to guide therapy. The and fusion genes present in supratentorial ependymomas are not directly targetable with agents in the clinic, but can provide leads for future research.

Clinical Features

The clinical presentation of ependymoma is dependent on tumor location.

Infratentorial (posterior fossa) ependymoma: In children, approximately 65% to 75% of ependymomas arise in the posterior fossa. Children with posterior fossa ependymoma may present with signs and symptoms of obstructive hydrocephalus due to obstruction at the level of the fourth ventricle. They may also present with ataxia, neck pain, or cranial nerve palsies.

Diagnostic Evaluation

Every patient suspected of having ependymoma is
evaluated with diagnostic imaging of the whole brain and spinal cord. The most
sensitive method available for evaluating spinal cord subarachnoid metastasis
is spinal magnetic resonance imaging (MRI) performed with gadolinium. This is ideally done before surgery to avoid confusion with postoperative blood. If MRI
is used, the entire spine is generally imaged in at least two planes with contiguous
MRI slices performed after gadolinium enhancement.

If feasible, CSF cytological evaluation is conducted.

Prognostic Factors

Unfavorable factors affecting outcome (except as noted) include the following:

Molecular characteristics.

Posterior fossa ependymoma can be divided into the following two groups based on distinctive patterns of gene expression.

EPN-PFA occurs primarily in young children and is characterized by a largely balanced genomic profile with an increased occurrence of chromosome 1q gain and expression of genes and proteins previously shown to be associated with poor prognosis, such as tenascin C and epidermal growth factor receptor.

In contrast, EPN-PFB occurs primarily in older children and adults and is characterized by a more favorable prognosis and by numerous cytogenetic abnormalities involving whole chromosomes or chromosomal arms.

Chromosome 1q25 gain, which is present in approximately 20% of ependymoma cases, is reported to be prognostic for inferior outcome for both posterior fossa ependymoma and supratentorial ependymoma. Other factors that have been reported to be associated with poor prognosis for pediatric ependymoma include expression of the enzymatic subunit of telomerase (hTERT) and expression of the neural stem cell marker Nestin.[]

Tumor location. Cranial variants of ependymoma have a less favorable outcome than primary spinal cord ependymomas. Location within the spinal cord may also affect outcome, with tumors in the lower portion of the spinal cord having a worse prognosis.[]

Younger age at diagnosis.[]

Anaplastic histology.[]; ; []; []

Subtotal resection.; []

Lower doses of radiation.

Immunohistochemical testing has identified increased expression of markers of proliferation (e.g., Ki-67 and MIB-1) and increased expression of EZH2, a polycomb complex protein involved in epigenetic regulation of gene expression, as prognostic factors for greater risk of treatment failure.

Follow-up After Treatment

Surveillance neuroimaging, coupled with clinical assessments, are generally recommended after treatment for ependymoma. The frequency and duration have been arbitrarily determined and the utility is uncertain. Most practitioners obtain MRI imaging of the brain and/or spinal cord every 3 months for the first 1 to 2 years after treatment. After 2 years, imaging every 6 months for the next 3 years is often undertaken.

Histopathologic Classification of Childhood Ependymal Tumors

For the first time, the 2016 World Health Organization (WHO) Classification of Tumors of the Central Nervous System (CNS) incorporates the addition of genotypic findings in the classification of select CNS tumors. This integrated classification is intended to define more homogeneous entities that will improve the accuracy of diagnoses, refine prognoses, and more reliably reach conclusions regarding treatment strategies.

Ependymal tumors are now classified into the following five main subtypes:

Subependymomas and myxopapillary ependymomas are usually considered to be clinically and pathologically distinct from the Grade II and Grade III ependymomas.

Although supratentorial and infratentorial ependymomas are believed to arise from radial glia cells, they have different genomic, gene expression, and immunohistochemical signatures. Supratentorial tumors are more often characterized by neuronal differentiation.

Ependymoblastoma is no longer recognized in the WHO classification and is now classified as an embryonal tumor with multilayered rosettes.

The pathologic
classification of pediatric brain tumors is a specialized area that is
evolving; review of the diagnostic tissue by a neuropathologist who
has particular expertise in this area is strongly recommended.

Stage Information for Childhood Ependymoma

Although there is no formal staging system, ependymomas can be divided into
supratentorial, infratentorial, and spinal tumors. Approximately 30% of childhood ependymomas arise in supratentorial regions of the brain and 70% arise in the posterior fossa. They usually originate in the
ependymal linings of ventricles or central canal or ventriculus terminalis of the spinal cord and have access to the cerebrospinal fluid. Therefore, these tumors may
spread throughout the neuraxis, although dissemination is noted in less than 10% of patients with Grade II and Grade III ependymomas. Myxopapillary ependymomas are more likely to disseminate to the nervous system early in the course of illness.

Treatment Option Overview for Childhood Ependymoma

Many of the improvements in survival in childhood cancer have been made as a
result of clinical trials that have attempted to improve on the best available,
accepted therapy. Clinical trials in pediatrics are designed to compare new
therapy with therapy that is currently accepted as standard. This comparison
may be done in a randomized study of two treatment arms or by evaluating a single
new treatment and comparing the results with those previously obtained with
existing therapy.

Because of the relative rarity of cancer in children, all patients with aggressive brain
tumors should be considered for entry into a clinical trial. To determine and
implement optimum treatment, treatment planning by a multidisciplinary team of
cancer specialists who have experience treating childhood brain tumors is
required. Radiation therapy of pediatric brain tumors is technically demanding and should be performed in centers that have experience in that
area to ensure optimal results.

Dramatic improvements in survival have been achieved for children and adolescents with cancer. Between 1975 and 2010, childhood cancer mortality decreased by more than 50%. Childhood and adolescent cancer survivors require close monitoring because cancer therapy side effects may persist or develop months or years after treatment. (Refer to the PDQ summary Late Effects of Treatment for Childhood Cancer for specific information about the incidence, type, and monitoring of late effects in childhood and adolescent cancer survivors.)

Treatment of Newly Diagnosed Childhood Subependymoma

Subependymomas are exceedingly rare in children and approaches to treatment have been inferred from the experience in the adult population.

Treatment of Newly Diagnosed Childhood Myxopapillary Ependymoma

Myxopapillary ependymomas, considered to be a histologic subtype of ependymoma, have a relatively high incidence of central nervous system tumor dissemination at diagnosis and at follow-up. Imaging of the complete craniospinal axis at the time of diagnosis and during follow-up is indicated.

Historically, the management of myxopapillary ependymoma (WHO Grade I) consisted of an attempt at en bloc resection of the tumor with no further treatment in the case of a gross-total resection.; [] However, based on the finding that dissemination of these tumors to other parts of the neuraxis can occur, particularly when complete resection is not obtained, and evidence that focal radiation therapy may improve progression-free survival, many practitioners now favor the use of radiation therapy after surgical resection of the primary mass.; []; []

Typically, all patients undergo surgery to remove the tumor. Whether additional treatment is given depends on the extent of tumor resection and whether there is disseminated disease.

Surgery

Surgery is
performed in an attempt at maximal tumor reduction. Evidence suggests that more extensive surgical resection is related to an improved rate of survival.; [] Magnetic resonance imaging (MRI) is performed postoperatively to confirm the extent of resection. If not performed preoperatively, MRI of the entire neuraxis to evaluate disease dissemination and cerebrospinal fluid cytopathology is performed.

Patients with residual tumor or disseminated
disease should be considered at high risk of relapse and may be treated on
protocols specifically designed for them. Those with no evidence of residual
tumor still have an approximate 20% to 40% relapse risk in spite of
postoperative radiation therapy.

Retrospective analysis of the outcome for patients with posterior fossa ependymoma (EPN-PFB) suggests that these patients might be sufficiently treated with gross-total resection alone, but this approach has not been tested in a prospective, randomized clinical trial.

Adjuvant Therapy

Treatment options for no residual disease, no disseminated disease

Radiation therapy

The traditional postsurgical treatment for these patients has been radiation
therapy consisting of 54 Gy to 59.4 Gy to the tumor bed for children aged 3 years and older. It is not necessary
to treat the entire CNS (whole brain and spine) because these tumors usually
recur initially at the local site.; [] When possible, patients should be treated in a
center experienced with the delivery of highly conformal radiation therapy (including intensity-modulated radiation therapy or charged-particle radiation therapy) to pediatric patients with brain tumors.

Evidence (radiation therapy):

Chemotherapy

There is no evidence to date that adjuvant
chemotherapy, including the use of myeloablative chemotherapy, improves the outcome for patients with totally resected, nondisseminated ependymoma. For this reason, current treatment approaches do not include chemotherapy as a standard component of primary therapy for children with newly diagnosed ependymomas that are completely resected.

A randomized trial evaluating the efficacy of postradiation chemotherapy in children who have had a gross-total resection is underway.

Treatment options for residual disease, no disseminated disease

Second-look surgery

Second-look surgery should be considered because patients who have complete
resections have better disease control. In some cases, further surgery can be undertaken after the initial attempted resection if the pediatric neurosurgeon believes that a gross-total resection could be obtained by an alternate surgical approach to the tumor. In other cases, further up-front surgery is not anticipated to result in a gross-total resection, therefore, adjuvant therapy is initiated with future consideration of second-look surgery.

Radiation therapy

The rationale for radiation therapy as described in the Treatment options for no residual disease, no disseminated disease subsection above also pertains to the treatment of children with residual, nondisseminated ependymoma. In patients with a subtotal resection, treatment with radiation therapy results in 3-year to 5-year PFS in 30% to 50% of patients, although the outcome for patients with residual tumor within the spinal canal may be better.

Preirradiation chemotherapy

One study demonstrated a benefit of preirradiation chemotherapy in children with near-total resection (>90% resection), with outcomes comparable to children achieving a gross-total resection followed by radiation therapy. The Children’s Oncology Group (COG) has completed a study of preirradiation chemotherapy in children with residual disease after up-front surgery to determine whether children treated with chemotherapy can achieve a complete response with chemotherapy or second-look surgery. Results are pending.

There is no evidence that high-dose chemotherapy with stem cell rescue is of any benefit.; []

Treatment options for CNS disseminated disease

Radiation therapy

Regardless of the degree of surgical
resection, these patients generally receive radiation therapy to the whole
brain and spine, along with boosts to local disease and bulk areas of
disseminated disease. The traditional local postsurgical radiation doses in
these patients have been 54 Gy to 55.8 Gy. Doses of approximately 36 Gy to
the entire neuraxis (i.e., the whole brain and spine) are also
administered but may be modulated depending on the age of the patient. Boosts
between 41.4 Gy and 50.4 Gy to bulk areas of spinal disease are
administered, with doses depending on the age of the patient and the location
of the tumor. However, there are no contemporary studies published to support this approach.

Chemotherapy

The role of chemotherapy in the management of children with disseminated ependymoma is unproven.

Treatment options for children younger than 3 years

Chemotherapy

Some, but not all, chemotherapy regimens induce objective responses in children younger than 3 years with newly diagnosed ependymoma. Up to 40% of infants and young children with totally resected disease may achieve long-term survival with chemotherapy alone.[]

Radiation therapy

Historically, postoperative radiation therapy was omitted for children younger than 3 years with ependymoma. The previous two COG studies have lowered the age limit for postoperative radiation therapy to age 1 year in an effort to improve outcomes for these younger children. The first of these two studies () is awaiting publication to provide evidence of the utility of this approach.

Evidence (radiation therapy):

Conformal radiation approaches, such as 3-dimensional conformal radiation therapy, that minimize damage to normal brain tissue and charged-particle radiation therapy, such as proton-beam therapy, are under evaluation for infants and children with ependymoma. When analyzing neurologic outcome after treatment of young children with ependymoma, it is important to consider that not all long-term deficits can be ascribed to radiation therapy because deficits may be present in young children before therapy begins. For example, the presence of hydrocephalus at diagnosis is associated with lower intelligence quotient as measured after surgical resection and before administration of radiation therapy.

The recently closed COG protocol ( [NCT00027846]) for children with ependymoma includes children aged 1 year and older. The trial is a prospective evaluation of postoperative radiation therapy. Results are forthcoming.

Early-phase therapeutic trials may be available for selected patients. These trials may be available via the COG, the Pediatric Brain Tumor Consortium, or other entities. Information about National Cancer Institute (NCI)–supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, refer to the ClinicalTrials.gov website.

The following is an example of a national and/or institutional clinical trial that is currently being conducted:

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

Treatment of Recurrent Childhood Ependymoma

Recurrence is not uncommon for all grades of ependymoma
and may develop many years after initial treatment. Late recurrence
beyond 10 to 15 years has been reported. Disease generally recurs at the
primary tumor site, although concomitant neuraxis dissemination may also be seen. Systemic
relapse is extremely rare. At time of relapse, a complete evaluation for
extent of recurrence is indicated for all patients.

Treatment options for recurrent childhood ependymoma include the following:

Surgery

The need for further surgical
intervention is individualized based on the following:

Extent of the tumor.

Length of time between initial treatment and the reappearance of the recurrent
lesion.

In some cases, surgically accessible lesions may be treated alternatively by radiation therapy.

Radiation Therapy and/or Chemotherapy

Patients with recurrent ependymomas should be
considered for treatment with the following modalities:[]

Regardless of treatment strategy, the prognosis for patients with recurrence is poor. Entry into
studies of novel therapeutic approaches should be considered.

Early-phase therapeutic trials may be available for selected patients. These trials may be available via the Children's Oncology Group (COG), the Pediatric Brain Tumor Consortium, or other entities. Information about National Cancer Institute (NCI)–supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, refer to the ClinicalTrials.gov website.

The following is an example of a national and/or institutional clinical trial that is currently being conducted:

(Pediatric MATCH: Targeted Therapy Directed by Genetic Testing in Treating Pediatric Patients with Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphomas, or Histiocytic Disorders): NCI-COG Pediatric Molecular Analysis for Therapeutic Choice (MATCH), referred to as Pediatric MATCH, will match targeted agents with specific molecular changes identified using a next-generation sequencing targeted assay of more than 3,000 different mutations across more than 160 genes in refractory and recurrent solid tumors. Children and adolescents aged 1 to 21 years are eligible for the trial.

Tumor tissue from progressive or recurrent disease must be available for molecular characterization. Patients with tumors that have molecular variants addressed by treatment arms included in the trial will be offered treatment on Pediatric MATCH. Additional information can be obtained on the ClinicalTrials.gov website for APEC1621 (NCT03155620).

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

Changes to This Summary (01/24/2018)

The PDQ cancer information summaries are reviewed regularly and updated as
new information becomes available. This section describes the latest
changes made to this summary as of the date above.

General Information About Childhood Ependymoma

Revised text to state that certain molecular characteristics may be unfavorable prognostic factors for pediatric ependymoma.

Added text to state that chromosome 1q25 gain, which is present in approximately 20% of ependymoma cases, is reported to be prognostic for inferior outcome for both posterior fossa ependymoma and supratentorial ependymoma (cited Andreiuolo et al. as reference 20).

This summary is written and maintained by the PDQ Pediatric Treatment Editorial Board, which is
editorially independent of NCI. The summary reflects an independent review of
the literature and does not represent a policy statement of NCI or NIH. More
information about summary policies and the role of the PDQ Editorial Boards in
maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® - NCI's Comprehensive Cancer Database pages.

About This PDQ Summary

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of childhood ependymoma. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.

Reviewers and Updates

This summary is reviewed regularly and updated as necessary by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

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Levels of Evidence

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